Publications by authors named "José A Lorente"

134 Publications

Cross-Resistance to Abiraterone and Enzalutamide in Castration Resistance Prostate Cancer Cellular Models Is Mediated by AR Transcriptional Reactivation.

Cancers (Basel) 2021 Mar 23;13(6). Epub 2021 Mar 23.

GENyO, Centre for Genomics and Oncological Research, Pfizer-University of Granada-Andalusian Regional Government, Gene Regulation, Stem Cells & Development Lab, PTS Granada, Avenida de la Ilustracion 114, 18016 Granada, Spain.

Androgen deprivation therapy (ADT) and novel hormonal agents (NHAs) (Abiraterone and Enzalutamide) are the goal standard for metastatic prostate cancer (PCa) treatment. Although ADT is initially effective, a subsequent castration resistance status (CRPC) is commonly developed. The expression of androgen receptor (AR) alternative splicing isoforms ( and ) has been associated to CRPC. However, resistance mechanisms to novel NHAs are not yet well understood. Androgen-dependent PCa cell lines were used to generate resistant models to ADT only or in combination with Abiraterone and/or Enzalutamide (concomitant models). Functional and genetic analyses were performed for each resistance model by real-time cell monitoring assays, flow cytometry and RT-qPCR. In androgen-dependent PCa cells, the administration of Abiraterone and/or Enzalutamide as first-line treatment involved a critical inhibition of AR activity associated with a significant cell growth inhibition. Genetic analyses on ADT-resistant PCa cell lines showed that the CRPC phenotype was accompanied by overexpression of full-length and AR target genes, but not necessarily and/or isoforms. These ADT resistant cell lines showed higher proliferation rates, migration and invasion abilities. Importantly, ADT resistance induced cross-resistance to Abiraterone and/or Enzalutamide. Similarly, concomitant models possessed an elevated expression of full-length and proliferation rates and acquired cross-resistance to its alternative NHA as second-line treatment.
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http://dx.doi.org/10.3390/cancers13061483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004828PMC
March 2021

Antioxidants for the Treatment of Breast Cancer: Are We There Yet?

Antioxidants (Basel) 2021 Jan 31;10(2). Epub 2021 Jan 31.

Instituto de Investigación Biosanitaria Ibs.GRANADA, University Hospitals of Granada-University of Granada, 18100 Granada, Spain.

Breast cancer is the most frequent cancer and the leading cause of cancer death in women. Oxidative stress and the generation of reactive oxygen species (ROS) have been related to cancer progression. Compared to their normal counterparts, tumor cells show higher ROS levels and tight regulation of REDOX homeostasis to maintain a low degree of oxidative stress. Traditionally antioxidants have been extensively investigated to counteract breast carcinogenesis and tumor progression as chemopreventive agents; however, there is growing evidence indicating their potential as adjuvants for the treatment of breast cancer. Aimed to elucidate whether antioxidants could be a reality in the management of breast cancer patients, this review focuses on the latest investigations regarding the ambivalent role of antioxidants in the development of breast cancer, with special attention to the results derived from clinical trials, as well as their potential use as plausible agents in combination therapy and their power to ameliorate the side effects attributed to standard therapeutics. Data retrieved herein suggest that antioxidants play an important role in breast cancer prevention and the improvement of therapeutic efficacy; nevertheless, appropriate patient stratification based on "redoxidomics" or tumor subtype is mandatory in order to define the dosage for future standardized and personalized treatments of patients.
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http://dx.doi.org/10.3390/antiox10020205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911462PMC
January 2021

Oxygen-sensitivity and Pulmonary Selectivity of Vasodilators as Potential Drugs for Pulmonary Hypertension.

Antioxidants (Basel) 2021 Jan 21;10(2). Epub 2021 Jan 21.

Department of Pharmacology and Toxicology, School of Medicine, University Complutense of Madrid, 28040 Madrid, Spain.

Current approved therapies for pulmonary hypertension (PH) aim to restore the balance between endothelial mediators in the pulmonary circulation. These drugs may exert vasodilator effects on poorly oxygenated vessels. This may lead to the derivation of blood perfusion towards low ventilated alveoli, i.e., producing ventilation-perfusion mismatch, with detrimental effects on gas exchange. The aim of this study is to analyze the oxygen-sensitivity in vitro of 25 drugs currently used or potentially useful for PH. Additionally, the study analyses the effectiveness of these vasodilators in the pulmonary the systemic vessels. Vasodilator responses were recorded in pulmonary arteries (PA) and mesenteric arteries (MA) from rats and in human PA in a wire myograph under different oxygen concentrations. None of the studied drugs showed oxygen selectivity, being equally or more effective as vasodilators under conditions of low oxygen as compared to high oxygen levels. The drugs studied showed low pulmonary selectivity, being equally or more effective as vasodilators in systemic than in PA. A similar behavior was observed for the members within each drug family. In conclusion, none of the drugs showed optimal vasodilator profile, which may limit their therapeutic efficacy in PH.
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http://dx.doi.org/10.3390/antiox10020155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911835PMC
January 2021

Liver-lung interactions in acute respiratory distress syndrome.

Intensive Care Med Exp 2020 Dec 18;8(Suppl 1):48. Epub 2020 Dec 18.

Department of Critical Care Medicine, Hospital Universitario de Getafe, Madrid, Spain.

Patients with liver diseases are at high risk for the development of acute respiratory distress syndrome (ARDS). The liver is an important organ that regulates a complex network of mediators and modulates organ interactions during inflammatory disorders. Liver function is increasingly recognized as a critical determinant of the pathogenesis and resolution of ARDS, significantly influencing the prognosis of these patients. The liver plays a central role in the synthesis of proteins, metabolism of toxins and drugs, and in the modulation of immunity and host defense. However, the tools for assessing liver function are limited in the clinical setting, and patients with liver diseases are frequently excluded from clinical studies of ARDS. Therefore, the mechanisms by which the liver participates in the pathogenesis of acute lung injury are not totally understood. Several functions of the liver, including endotoxin and bacterial clearance, release and clearance of pro-inflammatory cytokines and eicosanoids, and synthesis of acute-phase proteins can modulate lung injury in the setting of sepsis and other severe inflammatory diseases. In this review, we summarized clinical and experimental support for the notion that the liver critically regulates systemic and pulmonary responses following inflammatory insults. Although promoting inflammation can be detrimental in the context of acute lung injury, the liver response to an inflammatory insult is also pro-defense and pro-survival. A better understanding of the liver-lung axis will provide valuable insights into new diagnostic targets and therapeutic strategies for clinical intervention in patients with or at risk for ARDS.
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http://dx.doi.org/10.1186/s40635-020-00337-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746785PMC
December 2020

[ISAR Score (Identification of Seniors At Risk) predicts mortality in patients older than 75 years admitted in Intensive Care].

Rev Esp Geriatr Gerontol 2021 Jan-Feb;56(1):5-10. Epub 2020 Dec 11.

Servicio de Medicina Intensiva y Grandes Quemados, Hospital Universitario de Getafe, Getafe, Madrid, España; CIBER de Enfermedades Respiratorias, Madrid, Universidad Europea, Madrid, España.

Background And Objectives: Currently, the patient's baseline situation is a more important prognostic factor than age. The purpose of this study is to estimate the prognostic value of the ISAR score (Identification of Senior at Risk) in patients ≥75 years admitted to intensive care (ICU).

Patients And Methods: Prospective multicenter study including patients ≥75 years admitted to the ICU > 24hours. On admission, 28 days and 6 months after discharge from the ICU, mortality and baseline were evaluated using the ISAR score, the Lawton and Brody scale (LB) and the Barthel index (BI), the Frail fragility scale. scale (FS), the Charlson comorbidity index (ICC), Dementia rating score (DRC).

Results: 38 of 94 patients (40%) were high risk (ISAR ≥ 3) and were characterized by BI 90 (65-100), LB 4 (3-5), and CDR 1 (0-2), ICC 7.5 (6-10). 58% had FS ≥ 3. In the long term, they were in a situation of dependency [BI 50 (2.5-77.5), LB 3 (0-4), CDR 1 (0-1.5)]. The ICU mortality at 28 days and 6 months was 18.4%, 25.7% and 35.3%, respectively, being statistically significant. The area under the ISAR score ROC curve was 0.749 to 0.797, in all the mortality periods studied, although the difference with other predictive variables was not significant, but the p value was the lowest.

Conclusions: The ISAR score predicts mortality in critically elderly patients with a discriminative capacity comparable to other predictive variables.
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http://dx.doi.org/10.1016/j.regg.2020.09.009DOI Listing
December 2020

Sandwich-Type Electrochemical Paper-Based Immunosensor for Claudin 7 and CD81 Dual Determination on Extracellular Vesicles from Breast Cancer Patients.

Anal Chem 2021 01 10;93(2):1143-1153. Epub 2020 Dec 10.

INQUISAL, Departamento de Química, Universidad Nacional de San Luis, CONICET, Chacabuco 917, D5700BWS San Luis, Argentina.

This study is focused on identifying novel epithelial markers in circulating extracellular vesicles (EVs) through the development of a dual sandwich-type electrochemical paper-based immunosensor for Claudin 7 and CD81 determination, as well as its validation in breast cancer (BC) patients. This immunosensor allows for rapid, sensitive, and label-free detection of these two relevant BC biomarkers. Under optimum conditions, the limit of detection for Claudin 7 was 0.4 pg mL, with a wide linear range of 2 to 1000 pg mL, while for CD81, the limit of detection was 3 pg mL, with a wide linear range of 0.01 to 10 ng mL. Finally, we validated Claudin 7 and CD81 determination in EVs from 60 BC patients and 20 healthy volunteers, reporting higher diagnostic accuracy than the one observed with classical diagnostic markers. This analysis provides a low-cost, specific, versatile, and user-friendly strategy as a robust and reliable tool for early BC diagnosis.
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http://dx.doi.org/10.1021/acs.analchem.0c04180DOI Listing
January 2021

Strategies for Isolation and Phenotypic, Genetic, and Functional Characterization of Circulating Tumor Cells.

Cancers (Basel) 2020 Nov 4;12(11). Epub 2020 Nov 4.

Liquid Biopsy & Cancer Interception Group, GENYO Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain.

From the medical and scientific point of view, we are witnessing important changes in the way we approach diseases, and consequently in the way we manage patients [...].
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http://dx.doi.org/10.3390/cancers12113257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694253PMC
November 2020

Drug Repurposing for Triple-Negative Breast Cancer.

J Pers Med 2020 Oct 29;10(4). Epub 2020 Oct 29.

GENYO, Centre for Genomics and Oncological Research, Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, Avenida de la Ilustración, 18016 Granada, Spain.

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer which presents a high rate of relapse, metastasis, and mortality. Nowadays, the absence of approved specific targeted therapies to eradicate TNBC remains one of the main challenges in clinical practice. Drug discovery is a long and costly process that can be dramatically improved by drug repurposing, which identifies new uses for existing drugs, both approved and investigational. Drug repositioning benefits from improvements in computational methods related to chemoinformatics, genomics, and systems biology. To the best of our knowledge, we propose a novel and inclusive classification of those approaches whereby drug repurposing can be achieved in silico: structure-based, transcriptional signatures-based, biological networks-based, and data-mining-based drug repositioning. This review specially emphasizes the most relevant research, both at preclinical and clinical settings, aimed at repurposing pre-existing drugs to treat TNBC on the basis of molecular mechanisms and signaling pathways such as androgen receptor, adrenergic receptor, STAT3, nitric oxide synthase, or AXL. Finally, because of the ability and relevance of cancer stem cells (CSCs) to drive tumor aggressiveness and poor clinical outcome, we also focus on those molecules repurposed to specifically target this cell population to tackle recurrence and metastases associated with the progression of TNBC.
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http://dx.doi.org/10.3390/jpm10040200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711505PMC
October 2020

Precision Prevention and Cancer Interception: The New Challenges of Liquid Biopsy.

Cancer Discov 2020 Nov 9;10(11):1635-1644. Epub 2020 Oct 9.

Clinical and Translational Oncology Group, Clínica del Country, Bogotá, Colombia.

Despite major therapeutic progress, most advanced solid tumors are still incurable. Cancer interception is the active way to combat cancer onset, and development of this approach within high-risk populations seems a logical first step. Until now, strategies for the identification of high-risk subjects have been based on low-sensitivity and low-specificity assays. However, new liquid biopsy assays, "the Rosetta Stone of the new biomedicine era," with the ability to identify circulating biomarkers with unprecedented sensitivity, promise to revolutionize cancer management. This review focuses on novel liquid biopsy approaches and the applications to cancer interception. Cancer interception involves the identification of biomarkers associated with developing cancer, and includes genetic and epigenetic alterations, as well as circulating tumor cells and circulating epithelial cells in individuals at risk, and the implementation of therapeutic strategies to prevent the beginning of cancer and to stop its development. Large prospective studies are needed to confirm the potential role of liquid biopsy for early detection of precancer lesions and tumors.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0466DOI Listing
November 2020

High plasma levels of soluble P-Selectin and Factor VIII predict venous thromboembolism in non-small cell lung cancer patients: The Thrombo-Nsclc risk score.

Thromb Res 2020 12 16;196:349-354. Epub 2020 Sep 16.

Legal Medicine Department, School of Medicine, Av. Investigación, 11-PTS., Universidad de Granada, 18016 Granada, Spain.

Introduction: Venous thromboembolism (VTE) is common in non-small cell lung cancer (NSCLC) patients undergoing systemic chemotherapy. The usefulness of Khorana score (KRS) to predict risk in lung cancer patients is limited, and the identification of patients who would benefit most from thromboprophylaxis is challenging. We aimed to identify variables whose values before chemotherapy helped in predicting VTE occurrence, and build a model to assess VTE risk.

Materials And Methods: A cohort of newly diagnosed NSCLC patients to undergo outpatient chemotherapy, not under anticoagulant treatment, was recruited. Pre-chemotherapy demographic, clinical, analytical and tumor-specific variables were collected. Patients were prospectively followed-up for 12 months to record VTE events. Bivariate and multivariate analyses were performed to identify VTE-associated variables, and a prediction model was built and compared with KRS.

Results: 90 patients were recruited, 18 of whom had a VTE event during follow-up. High baseline levels of factor VIII (FVIII) and, especially, soluble P-selectin (sP-selectin), were independently associated with VTE risk (hazard ratio [HR] 4.15, 95% confidence interval [CI] 1.17-14.71, and 66.40 [8.70-506.69], respectively). Our so-called Thrombo-NSCLC risk score, which assigns 1 and 3 points to high FVIII and sP-selectin values, respectively, was significantly better than KRS in predicting VTE (area under the curve [AUC] 0.93 vs. 0.55, sensitivity 94.4 vs. 35.0%, specificity 93.1 vs. 60.0%). Our prediction model showed significant discriminating capacity between high risk vs. intermediate/low risk patients, while KRS did not.

Conclusions: The Thrombo-NSCLC risk score may be useful to identify those NSCLC patients who would benefit most from thromboprophylaxis.
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http://dx.doi.org/10.1016/j.thromres.2020.09.021DOI Listing
December 2020

DatAC: A visual analytics platform to explore climate and air quality indicators associated with the COVID-19 pandemic in Spain.

Sci Total Environ 2021 Jan 4;750:141424. Epub 2020 Aug 4.

GENYO, Centre for Genomics and Oncological Research: Pfizer/University of Granada/Andalusian Regional Government, PTS Granada, 18016 Granada, Spain; Department of Statistics, University of Granada, 18071 Granada, Spain. Electronic address:

The coronavirus disease 2019 (COVID-19) pandemic has caused an unprecedented global health crisis, with several countries imposing lockdowns to control the coronavirus spread. Important research efforts are focused on evaluating the association of environmental factors with the survival and spread of the virus and different works have been published, with contradictory results in some cases. Data with spatial and temporal information is a key factor to get reliable results and, although there are some data repositories for monitoring the disease both globally and locally, an application that integrates and aggregates data from meteorological and air quality variables with COVID-19 information has not been described so far to the best of our knowledge. Here, we present DatAC (Data Against COVID-19), a data fusion project with an interactive web frontend that integrates COVID-19 and environmental data in Spain. DatAC is provided with powerful data analysis and statistical capabilities that allow users to explore and analyze individual trends and associations among the provided data. Using the application, we have evaluated the impact of the Spanish lockdown on the air quality, observing that NO, CO, PM, PM and SO levels decreased drastically in the entire territory, while O levels increased. We observed similar trends in urban and rural areas, although the impact has been more important in the former. Moreover, the application allowed us to analyze correlations among climate factors, such as ambient temperature, and the incidence of COVID-19 in Spain. Our results indicate that temperature is not the driving factor and without effective control actions, outbreaks will appear and warm weather will not substantially limit the growth of the pandemic. DatAC is available at https://covid19.genyo.es.
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http://dx.doi.org/10.1016/j.scitotenv.2020.141424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399783PMC
January 2021

Corrigendum to "Challenges and opportunities of cfDNA analysis implementation in clinical practice: Perspective of the International Society of Liquid Biopsy (ISLB)" [Crit. Rev. Oncol. Hematol. 151 (July) (2020) 102978].

Crit Rev Oncol Hematol 2020 Oct 18;154:103058. Epub 2020 Aug 18.

Centre for Genomics and Oncological Research - GENYO, Pfizer, University of Granada, Andalusian Regional Government, Granada, Spain; Bio-Health Research Institute (Instituto de Investigación Biosanitaria ibs. GRANADA), Spain; Complejo Hospitalario Universitario Granada (CHUG), Department of Medical Oncology, University of Granada, Granada, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.critrevonc.2020.103058DOI Listing
October 2020

Challenges and opportunities of cfDNA analysis implementation in clinical practice: Perspective of the International Society of Liquid Biopsy (ISLB).

Crit Rev Oncol Hematol 2020 Jul 5;151:102978. Epub 2020 May 5.

Centre for Genomics and Oncological Research - GENYO, Pfizer, University of Granada, Andalusian Regional Government, Granada, Spain; Bio-Health Research Institute (Instituto de Investigación Biosanitaria ibs. GRANADA), Spain; Complejo Hospitalario Universitario Granada (CHUG), Department of Medical Oncology, University of Granada, Granada, Spain. Electronic address:

Precision medicine was born with the development of new diagnostic techniques and targeted drugs, yielding better outcomes in cancer care. With the evolution and increasing sensitivity for detecting oncogenic drivers, liquid biopsies (LBs), specifically cell-free DNA (cfDNA) analysis, have been proposed as a minimally-invasive technique for genomic profiling. Ranging from sequencing techniques to PCR-based methods and other more complex strategies, this approach, currently applicable in some solid tumors with robust evidence, is showing promising opportunities in other cancers. However, difficulties in validating their clinical utility exist within limitation at different levels among several techniques, reporting of the results, lack of appropriate clinical trial designs, and unknown economic impact. One of the aims of the ISLB is to create recommendations to develop reliable and sustainable diagnostic, prognostic and predictive tools using LBs. This paper is addressing these objectives, helping the healthcare providers and scientific community to understand the potential of LB.
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http://dx.doi.org/10.1016/j.critrevonc.2020.102978DOI Listing
July 2020

A Legal and Forensic Medicine Approach to Police Physical Intervention Techniques in High-Risk Situations.

Int J Environ Res Public Health 2020 04 19;17(8). Epub 2020 Apr 19.

Department of Physical Chemistry, Faculty of Sciences, INBIO, University of Cadiz, 11510 Puerto Real, Spain.

: The physical intervention techniques (PITs) typically used by the police in troublesome situations are examined in terms of injuring potential depending on whether they target a body zone of high, medium or low vulnerability. Based on legal and forensic considerations, and principles of congruence, opportunity and proportionality, a need exists to favor opponent locking and arrest techniques targeting non-vulnerable zones to minimize the risk of severe damage. : A search of the training manuals for the different kind of law of enforcement officers was carried out. Revision of injuries was available from electronic databases of academic o medical journals. : Three different locking and arrest PITs based on operational tactical procedures (OTP) that avoid zones of high or medium vulnerability are proposed. The new techniques use blocking, diverting and grabbing of the upper and lower limbs, followed by dislocation and locking of the same targets. : The damaging potential of such PITs was assessed in terms of anatomical region and most were found to have a high risk of severe damage. The alternative PITs proposed here, which rely on OTP, improve in legal and forensic medical terms on existing choices and dramatically reduce the risk of injuring arrestees.
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http://dx.doi.org/10.3390/ijerph17082809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215352PMC
April 2020

Efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in mechanically ventilated intensive care patients-a randomized clinical trial.

Crit Care 2020 03 4;24(1):74. Epub 2020 Mar 4.

Centro de Investigacion Biomedica en Red (CIBERES), Hospital Universitari Vall d'Hebron, Barcelona, Spain.

Background: Pseudomonas aeruginosa infections are a serious threat in intensive care units (ICUs). The aim of this confirmatory, randomized, multicenter, placebo-controlled, double-blind, phase 2/3 study was to assess the efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in non-surgical ICU patients.

Methods: Eight hundred patients aged 18 to 80 years admitted to the ICU with expected need for mechanical ventilation for ≥ 48 h were randomized 1:1 to either IC43 100 μg or saline placebo, given in two vaccinations 7 days apart. The primary efficacy endpoint was all-cause mortality in patients 28 days after the first vaccination. Immunogenicity and safety were also evaluated.

Findings: All-cause mortality rates at day 28 were 29.2% vs 27.7% in the IC43 and placebo groups, respectively (P = .67). Overall survival (Kaplan-Meier survival estimates, P = .46) and proportion of patients with ≥ one confirmed P. aeruginosa invasive infection or respiratory tract infection also did not differ significantly between both groups. The geometric mean fold increase in OprF/I titers was 1.5 after the first vaccination, 20 at day 28, after the second vaccination, and 2.9 at day 180. Significantly more patients in the placebo group (96.5%) had ≥ one adverse event (AE) versus the IC43 100 μg group (93.1%) (P = .04). The most frequently reported severe AEs in the IC43 and placebo groups were respiratory failure (6.9% vs 5.7%, respectively), septic shock (4.1% vs 6.5%), cardiac arrest (4.3% vs 5.7%), multiorgan failure (4.6% vs 5.5%), and sepsis (4.6% vs 4.2%). No related serious AEs were reported in the IC43 group.

Interpretation: The IC43 100 μg vaccine was well tolerated in this large population of medically ill, mechanically ventilated patients. The vaccine achieved high immunogenicity but provided no clinical benefit over placebo in terms of overall mortality.

Trial Registration: https://clinicaltrials.gov (NCT01563263). Registration was sent to ClinicalTrials.gov on March 14, 2012, but posted by ClinicalTrials.gov on March 26, 2012. The first subject was included in the trial on March 22, 2012.
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http://dx.doi.org/10.1186/s13054-020-2792-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057595PMC
March 2020

Histopathological changes of organ dysfunction in sepsis.

Intensive Care Med Exp 2019 Jul 25;7(Suppl 1):45. Epub 2019 Jul 25.

Hospital Universitario de Getafe, Madrid, Spain.

Background: Sepsis is a highly lethal disorder. Organ dysfunction in sepsis is not defined as a clinicopathological entity but rather by changes in clinical, physiological, or biochemical parameters. Pathogenesis and specific treatment of organ dysfunction in sepsis are unknown. The study of the histopathological correlate of organ dysfunction in sepsis will help understand its pathogenesis.

Methods: We searched in PubMed, EMBASE, and Scielo for original articles on kidney, brain, and liver dysfunction in human sepsis. A defined search strategy was designed, and pertinent articles that addressed the histopathological changes in sepsis were retrieved for review. Only studies considered relevant in the field were discussed.

Results: Studies on acute kidney injury (AKI) in sepsis reveal that acute tubular necrosis is less prevalent than other changes, indicating that kidney hypoperfusion is not the predominant pathogenetic mechanism of sepsis-induced AKI. Other more predominant histopathological changes are apoptosis, interstitial inflammation, and, to a lesser extent, thrombosis. Brain pathological findings include white matter hemorrhage and hypercoagulability, microabscess formation, central pontine myelinolysis, multifocal necrotizing leukoencephalopathy, metabolic changes, ischemic changes, and apoptosis. Liver pathology in sepsis includes steatosis, cholangiolitis and intrahepatic cholestasis, periportal inflammation, and apoptosis. There is no information on physiological or biochemical biomarkers of the histopathological findings.

Conclusions: Histopathological studies may provide important information for a better understanding of the pathogenesis of organ dysfunction in sepsis and for the design of potentially effective therapies. There is a lack of clinically available biomarkers for the identification of organ dysfunction as defined by the histological analysis.
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http://dx.doi.org/10.1186/s40635-019-0236-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658642PMC
July 2019

Why translational research matters: proceedings of the third international symposium on acute lung injury translational research (INSPIRES III).

Intensive Care Med Exp 2019 Jul 25;7(Suppl 1):40. Epub 2019 Jul 25.

Servicio de Medicina Intensiva, Hospital Universitario de Getafe, Madrid, Spain.

Current treatment of acute respiratory distress syndrome (ARDS) in critically ill patients is limited to supportive measures including mechanical ventilation. It is our view that effective therapies for ARDS can only be found through experimental and translational science that seeks to better understand the mechanisms of injury and identify therapeutic approaches, using pre-clinical models of acute lung injury that closely mimic the clinical syndrome of ARDS. This editorial gives examples of ways in which translational science contributes to the development of more specific measures against ARDS in the critically ill. In order to improve focus on this essential research as well as to enhance collaborative research efforts, a Translational Biology Group was founded within the European Society of Intensive Care Medicine. INSPIRES is an international symposium on translational research in lung injury as well as in other areas of critical illness, intended to serve as a platform for the translational biology working group. This issue of ICMx is dedicated to the proceedings of INSPIRES III.
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http://dx.doi.org/10.1186/s40635-019-0230-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658622PMC
July 2019

EGFR detection in extracellular vesicles of breast cancer patients through immunosensor based on silica-chitosan nanoplatform.

Talanta 2019 Mar 13;194:243-252. Epub 2018 Oct 13.

INQUISAL, Departamento de Química, Universidad Nacional de San Luis, CONICET, Chacabuco 917, D5700BWS San Luis, Argentina. Electronic address:

In the present work, we designed a microfluidic electrochemical immunosensor with enough sensibility and precision to quantify epithermal growth factor receptor (EGFR) in plasma extracellular vesicles (EVs) of plasma from breast cancer patients. The sensor employs SiNPs coated with chitosan (SiNPs-CH) as reaction's platform, based on the covalently immobilization of monoclonal anti-EGFR on SiNPs-CH retained in the central channel (CC) of the microfluidic device. The synthetized SiNPs-CH were characterized by UV-visible spectroscopy (UV-visible), energy dispersive spectrometry (EDS), Nanoparticle Tracking Analysis (NTA) and transmission electron microscopy (TEM). EGFR was quantified by a direct sandwich immunoassay measuring through a horseradish peroxidase (HRP)-conjugated anti-EGFR. The enzymatic product (benzoquinone) was detected by reduction at - 100 mV on a sputtering gold electrode. The measured current was directly proportional to the level of EGFR in human serum samples. The linear range was from 0 ng mL to 50 ng mL. The detection limit was 1.37 pg mL, and the within- and between-assay coefficients of variation were below 6.25%. Finally, plasma samples from 30 early breast cancer patients and 20 healthy donor were analyzed by the novel method. EGFR levels in EVs (EVs-EGFR) were significantly higher than in the healthy control group (p = 0.002) and also, more sensitivity and specificity than normal serum markers like CEA and CA15.3 has been observed. EVs-EGFR concentration correlates with EGFR tumor status (p = 0.0003) as well as it correlate with the tumor size and pathological grade. To conclude, plasma EVs are suitable for proteomic characterization of cancer disease, as long as the employed method has sufficient sensitivity, like the case of immune-electrochemical nanosensors with incremented reaction surface.
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http://dx.doi.org/10.1016/j.talanta.2018.10.016DOI Listing
March 2019

GSTM1 gene expression and copy number variation in prostate cancer patients-Effect of chemical exposures and physical activity.

Urol Oncol 2019 04 28;37(4):290.e9-290.e15. Epub 2018 Dec 28.

GENYO (Pfizer-University of Granada-Andalusian Government Centre for Genomics and Oncological Research), Granada, Spain; University of Granada, Department of Biochemistry and Molecular Biology III, Faculty of Medicine, PTS, Granada, Spain.

Background: Many etiological factors have been related to prostate cancer (CaP) development, progression, and survival, such as age, population origin, geographic area, occupational exposures, and nutrition and lifestyle factors. However, physical activity affords health benefits to cancer patients, including those with CaP. Glutathione S-Transferases enzymes have been linked to CaP because of their role in the detoxification of a wide variety of potential carcinogens, steroid hormones and xenobiotics. Among the different glutathione S-transferases isoforms, null genotype for GSTM1 has been associated with an increased risk of CaP, although data are controversial. As the relationship between copy number variation and gene expression of GSTM1 in CaP remains unexplored, this study analyzed GSTM1 gene expression and/or dosage effect on CaP risk and aggressiveness. The potential protective role of physical activity was also explored.

Methods: Three hundred and seventeen patients (159 non-CaP and 158 CaP) were recruited from the Service of Urology (Hospital Virgen de las Nieves, Granada, Spain) over the period 2012 to 2014 and were followed-up until January 2018 to ensure a correct classification of control and patients. Individuals were classified in each group based on histological analysis of tissue biopsy, along with data on PSA level, Gleason score and T stage in patients with biopsies positive for CaP. Individuals with a negative biopsy were considered as controls. All controls underwent a systematic 20-core ultrasound guided biopsy in order to limit the false negative rate. Genomic DNA was extracted from peripheral blood to determine the exact copy numbers of GSTM1, and RNA was extracted from prostate tissue samples to determine GSTM1 gene expression. Both analyses were performed using the qPCR method. A questionnaire was administered to all patients to assess environmental exposures, lifestyle, and physical activity. The association of GSTM1 copy number variation and expression with the rest of variables was assessed by chi-square test and the Mann-Whitney test. Multiple logistic regression was used to assess which factors were associated with the risk of CaP.

Results: The presence of 1 or 2 copies of the GSTM1 gene was not less prevalent in CaP compared to non-CaP patients; however, a significant decreased GSTM1 gene expression was observed in CaP tissue relative to non-CaP tissue (P = 0.003). CaP patients with environmental exposure to dust and smoke, and smoking habit had a significantly decreased GSTM1 gene expression (and near-significantly decreased for living in urban areas) as compared to non-CaP patients with the same exposures. In addition, physical activity was significantly associated with a lower risk of CaP (P = 0.006) and with increased GSTM1 gene expression (P = 0.002).

Conclusions: A reduced GSTM1 gene expression in prostate tissue was observed in CaP patients with some environmental chemical exposures. Intriguingly, physical activity might play a protective role against CaP development, possibly as a result of increasing GSTM1 gene expression in prostate tissue. However, this observation warrants further confirmation.
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http://dx.doi.org/10.1016/j.urolonc.2018.12.010DOI Listing
April 2019

Hydroxytyrosol inhibits cancer stem cells and the metastatic capacity of triple-negative breast cancer cell lines by the simultaneous targeting of epithelial-to-mesenchymal transition, Wnt/β-catenin and TGFβ signaling pathways.

Eur J Nutr 2019 Dec 21;58(8):3207-3219. Epub 2018 Nov 21.

UGC de Oncología Médica, Complejo Hospitalario de Jaén, Avenida del Ejército Español 10, Jaén, Spain.

Purpose: This study was aimed to determine the impact of hydroxytyrosol (HT), a minor compound found in olive oil, on breast cancer stem cells (BCSCs) and the migration capacity of triple-negative breast cancer (TNBC) cell lines through the alteration of epithelial-to-mesenchymal transition (EMT) and embryonic signaling pathways.

Methods: BCSCs self-renewal was determined by the mammosphere-forming efficiency in SUM159PT, BT549, MDA-MB-231 and Hs578T TNBC cell lines. Flow cytometric analysis of CD44/CD24 and aldehyde dehydrogenase positive (ALDH) subpopulations, migration by the "wound healing assay", invasion and Western blot of EMT markers and TGFβ signaling were investigated in SUM159PT, BT549 and MDA-MB-231 cell lines. Wnt/β-catenin signaling was assessed by Western blot in BT549 cells expressing WNT1 and MDA-MB-231 cells. Changes in TGFβ activity was determined by SMAD Binding Element (SBE) reporter assay.

Results: HT reduced BCSCs self-renewal, ALDH (aldehyde dehydrogenase) and CD44/CD24 subpopulations, tumor cell migration and invasion. Consistently, HT suppressed Wnt/β-catenin signaling by decreasing p-LRP6, LRP6, β-catenin and cyclin D1 protein expression and the EMT markers SLUG, ZEB1, SNAIL and VIMENTIN. Finally, HT inhibited p-SMAD2/3 and SMAD2/3 in SUM159PT, BT549 and MDA-MB-231 cells, what was correlated with a less TGFβ activity.

Conclusion: In conclusion, we report for the first time the inhibitory role of HT on BCSCs and tumor cell migration by targeting EMT, Wnt/β-catenin and TGFβ signaling pathways. Our findings highlight the importance of the chemopreventive compound HT as a novel candidate to be investigated as an alternative targeted therapy for TNBC.
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http://dx.doi.org/10.1007/s00394-018-1864-1DOI Listing
December 2019

Influenza A: New Therapeutic Targets for a Deadly Disease.

Arch Bronconeumol 2019 06 5;55(6):295-296. Epub 2018 Nov 5.

Hospital Universitario de Getafe, Madrid, Spain; CIBER de Enfermedades Respiratorias, Spain; Universidad Europea, Madrid, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.arbres.2018.09.020DOI Listing
June 2019

Identification of novel metabolomic biomarkers in an experimental model of septic acute kidney injury.

Am J Physiol Renal Physiol 2019 01 31;316(1):F54-F62. Epub 2018 Oct 31.

CIBER de Enfermedades Respiratorias, CIBERES, Madrid , Spain.

The aim of this study is the identification of metabolomic biomarkers of sepsis and sepsis-induced acute kidney injury (AKI) in an experimental model. Pigs were anesthetized and monitored to measure mean arterial pressure (MAP), systemic blood flow (Q), mean pulmonary arterial pressure, renal artery blood flow (Q), renal cortical blood flow (Q), and urine output (UO). Sepsis was induced at t = 0 min by the administration of live Escherichia coli ( n = 6) or saline ( n = 8). At t = 300 min, animals were killed. Renal tissue, urine, and serum samples were analyzed by nuclear magnetic resonance (NMR) spectroscopy. Principal component analyses were performed on the processed NMR spectra to highlight kidney injury biomarkers. Sepsis was associated with decreased Q and MAP and decreased Q, Q, and UO. Creatinine serum concentration and neutrophil gelatinase-associated lipocalin (NGAL) serum and urine concentrations increased. NMR-based metabolomics analysis found metabolic differences between control and septic animals: 1) in kidney tissue, increased lactate and nicotinuric acid and decreased valine, aspartate, glucose, and threonine; 2) in urine, increased isovaleroglycine, aminoadipic acid, N-acetylglutamine, N-acetylaspartate, and ascorbic acid and decreased myoinositol and phenylacetylglycine; and 3) in serum, increased lactate, alanine, pyruvate, and glutamine and decreased valine, glucose, and betaine concentrations. The concentration of several metabolites altered in renal tissue and urine samples from septic animals showed a significant correlation with markers of AKI (i.e., creatinine and NGAL serum concentrations). NMR-based metabolomics is a potentially useful tool for biomarker identification of sepsis-induced AKI.
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http://dx.doi.org/10.1152/ajprenal.00315.2018DOI Listing
January 2019

Circulating tumor cells criteria (CyCAR) versus standard RECIST criteria for treatment response assessment in metastatic colorectal cancer patients.

J Transl Med 2018 09 6;16(1):251. Epub 2018 Sep 6.

Integral Oncology Division, Clinical University Hospital, Av. Dr. Olóriz 16, 18012, Granada, Spain.

Background: The use of circulating tumor cells (CTCs) as indicators of treatment response in metastatic colorectal cancer (mCRC) needs to be clarified. The objective of this study is to compare the Response Evaluation Criteria in Solid Tumors (RECIST) with the Cytologic Criteria Assessing Response (CyCAR), based on the presence and phenotypic characterization of CTCs, as indicators of FOLFOX-bevacizumab treatment response.

Methods: 77 mCRC blood samples from FOLFOX-bevacizumab treated patients were analyzed to isolate CTCs before and after (12 and 24 weeks) treatment, using an immunomagnetic separation method. VEGFR expression was identified by double immunostaining.

Results: We observed a decrease of CTCs (42.8 vs. 18.2%) and VEGFR positivity (69.7% vs. 41.7%) after treatment. According to RECIST, 6.45% of the patients did not show any clinical benefit, whereas 93.55% patients showed a favorable response at 12 weeks. According to CyCAR, 29% had a non-favorable response and 71% patients did not. No significant differences were found between the response assessment by RECIST and CyCAR at 12 or 24 weeks. However, in the multivariate analysis, RECIST at 12 weeks and CyCAR at 24 weeks were independent prognostic factors for OS (HR: 0.1, 95% CI 0.02-0.58 and HR: 0.35, 95% CI 0.12-0.99 respectively).

Conclusions: CyCAR results were comparable to RECIST in evaluating the response in mCRC and can be used as an alternative when the limitation of RECIST requires additional response analysis techniques.
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http://dx.doi.org/10.1186/s12967-018-1624-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6127986PMC
September 2018

Hemodynamic management of critically ill burn patients: an international survey.

Crit Care 2018 08 17;22(1):194. Epub 2018 Aug 17.

Department of Anesthesiology and Critical Care and Burn Unit, AP-HP, Hôpital Saint-Louis, Hôpital Lariboisière, UMR Institut National de la Santé et de la Recherche Médicale (INSERM) 942, Université Paris Diderot, F-75475, Paris, France.

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http://dx.doi.org/10.1186/s13054-018-2129-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097223PMC
August 2018

Activating Transcription Factor 4 Modulates TGFβ-Induced Aggressiveness in Triple-Negative Breast Cancer via SMAD2/3/4 and mTORC2 Signaling.

Clin Cancer Res 2018 11 16;24(22):5697-5709. Epub 2018 Jul 16.

UGC de Oncología Médica, Complejo Hospitalario de Jaén, Jaén, Spain.

On the basis of the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFβ1. is overexpressed in patients with triple-negative breast cancer (TNBC), but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine effects on patients with breast cancer survival and TNBC aggressiveness, and the relationships between TGFβ and ATF4. Defining the signaling pathways may help us identify a cell signaling-tailored gene signature. Patient survival data were determined by Kaplan-Meier analysis. Relationship between TGFβ and ATF4, their effects on aggressiveness (tumor proliferation, metastasis, and stemness), and the underlying pathways were analyzed in three TNBC cell lines and using patient-derived xenografts (PDX). overexpression correlated with TNBC patient survival decrease and a SMAD-dependent crosstalk between ATF4 and TGFβ was identified. expression inhibition reduced migration, invasiveness, mammosphere-forming efficiency, proliferation, epithelial-mesenchymal transition, and antiapoptotic and stemness marker levels. In PDX models, silencing decreased metastases, tumor growth, and relapse after chemotherapy. ATF4 was shown to be active downstream of SMAD2/3/4 and mTORC2, regulating TGFβ/SMAD and mTOR/RAC1-RHOA pathways independently of stress. We defined an eight-gene signature with prognostic potential, altered in 45% of 2,509 patients with breast cancer. ATF4 may represent a valuable prognostic biomarker and therapeutic target in patients with TNBC, and we identified a cell signaling pathway-based gene signature that may contribute to the development of combinatorial targeted therapies for breast cancer. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3125DOI Listing
November 2018

MicroRNAs as biomarkers of acute lung injury.

Ann Transl Med 2018 Jan;6(2):34

Department of Critical Care, Hospital Universitario de Getafe, Madrid, Spain.

Acute respiratory distress syndrome (ARDS) is a common and complex inflammatory lung diseases affecting critically ill patients requiring mechanical ventilation. MicroRNAs (miRNAs), a novel pathway of non-coding RNA molecules that regulate gene expression at the post-transcriptional level, have emerged as a novel class of gene expression, and can play important roles in inflammation or apoptosis, which are common manifestations of ARDS and diffuse alveolar damage (DAD). In the present review, we discuss the role of miRNAs as biomarkers of ARDS and DAD, and their potential use as therapeutic targets for this condition.
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http://dx.doi.org/10.21037/atm.2018.01.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799140PMC
January 2018

Toxic epidermal necrolysis: a paradigm of critical illness.

Rev Bras Ter Intensiva 2017 Oct-Dec;29(4):499-508

Instituto de Investigación Sanitaria del Hospital Universitario de Getafe - Madrid, Spain.

Toxic epidermal necrolysis is an adverse immunological skin reaction secondary in most cases to the administration of a drug. Toxic epidermal necrolysis, Stevens-Johnson syndrome, and multiform exudative erythema are part of the same disease spectrum. The mortality rate from toxic epidermal necrolysis is approximately 30%. The pathophysiology of toxic epidermal necrolysis is similar in many respects to that of superficial skin burns. Mucosal involvement of the ocular and genital epithelium is associated with serious sequelae if the condition is not treated early. It is generally accepted that patients with toxic epidermal necrolysis are better treated in burn units, which are experienced in the management of patients with extensive skin loss. Treatment includes support, elimination, and coverage with biosynthetic derivatives of the skin in affected areas, treatment of mucosal involvement, and specific immunosuppressive treatment. Of the treatments tested, only immunoglobulin G and cyclosporin A are currently used in most centers, even though there is no solid evidence to recommend any specific treatment. The particular aspects of the treatment of this disease include the prevention of sequelae related to the formation of synechiae, eye care to prevent serious sequelae that can lead to blindness, and specific immunosuppressive treatment. Better knowledge of the management principles of toxic epidermal necrolysis will lead to better disease management, higher survival rates, and lower prevalence of sequelae.
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http://dx.doi.org/10.5935/0103-507X.20170075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5764563PMC
August 2018

Metabolomic Profile of ARDS by Nuclear Magnetic Resonance Spectroscopy in Patients With H1N1 Influenza Virus Pneumonia.

Shock 2018 11;50(5):504-510

CIBER de Enfermedades Respiratorias (CIBERES), Madrid, Spain.

Purpose: The integrated analysis of changes in the metabolic profile could be critical for the discovery of biomarkers of lung injury, and also for generating new pathophysiological hypotheses and designing novel therapeutic targets for the acute respiratory distress syndrome (ARDS). This study aimed at developing a nuclear magnetic resonance (NMR)-based approach for the identification of the metabolomic profile of ARDS in patients with H1N1 influenza virus pneumonia.

Methods: Serum samples from 30 patients (derivation set) diagnosed of H1N1 influenza virus pneumonia were analyzed by unsupervised principal component analysis to identify metabolic differences between patients with and without ARDS by NMR spectroscopy. A predictive model of partial least squares discriminant analysis (PLS-DA) was developed for the identification of ARDS. PLS-DA was trained with the derivation set and tested in another set of samples from 26 patients also diagnosed of H1N1 influenza virus pneumonia (validation set).

Results: Decreased serum glucose, alanine, glutamine, methylhistidine and fatty acids concentrations, and elevated serum phenylalanine and methylguanidine concentrations, discriminated patients with ARDS versus patients without ARDS. PLS-DA model successfully identified the presence of ARDS in the validation set with a success rate of 92% (sensitivity 100% and specificity 91%). The classification functions showed a good correlation with the Sequential Organ Failure Assessment score (R = 0.74, P < 0.0001) and the PaO2/FiO2 ratio (R = 0.41, P = 0.03).

Conclusions: The serum metabolomic profile is sensitive and specific to identify ARDS in patients with H1N1 influenza A pneumonia. Future studies are needed to determine the role of NMR spectroscopy as a biomarker of ARDS.
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http://dx.doi.org/10.1097/SHK.0000000000001099DOI Listing
November 2018

Predictors of diffuse alveolar damage in patients with acute respiratory distress syndrome: a retrospective analysis of clinical autopsies.

Crit Care 2017 Oct 20;21(1):254. Epub 2017 Oct 20.

Departamento de Cuidados Intensivos, Hospital Universitario de Getafe, Madrid, Spain.

Background: Although diffuse alveolar damage (DAD) is considered the typical histological pattern of acute respiratory distress syndrome (ARDS), only half of patients exhibit this morphological hallmark. Patients with DAD may have higher mortality than those without DAD. Therefore, we aimed to identify the factors associated with DAD in patients with ARDS.

Methods: We analyzed autopsy samples of 356 patients who had ARDS at the time of death. DAD was assessed by two pathologists, and ARDS criteria were evaluated by two intensivists. Criteria for severe ARDS included the degree of hypoxemia and the ancillary variables of the current Berlin definition assessed within 48 h before death: radiographic severity, high positive end-expiratory pressure (PEEP) level, and physiological variables (i.e., altered respiratory system compliance and large anatomic dead space).

Results: After multivariable analysis, high PEEP levels, physiological variables, and opacities involving only three quadrants on chest radiographs were not associated with DAD. The four markers independently associated with DAD were (1) duration of evolution (OR 3.29 [1.95-5.55] for patients with ARDS ≥ 3 days, p < 0.001), (2) degree of hypoxemia (OR 3.92 [1.48-10.3] for moderate ARDS and 6.18 [2.34-16.3] for severe ARDS, p < 0.01 for both), (3) increased dynamic driving pressure (OR 1.06 [1.04-1.09], p = 0.007), and (4) radiographic severity (OR 2.91 [1.47-5.75] for patients with diffuse opacities involving the four quadrants, p = 0.002). DAD was found in two-thirds of patients with a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen ≤ 100 mmHg and opacities involving the four quadrants.

Conclusions: In addition to severe hypoxemia, diffuse opacities involving the four quadrants were a strong marker of DAD.
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http://dx.doi.org/10.1186/s13054-017-1852-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5649062PMC
October 2017